the AdoCbl cofactor in the active site of methylmalonyl CoA. AdoCbl is composed of a central cobalt-containing corrin ring, an upper axial ligand (β-axial ligand), and a lower axial ligand (α-axial ligand). In methylmalonyl-CoA mutase, the β-axial ligand 5’-deoxy-5’-adenosine reversibly dissociated to give the deoxyadenosyl radical. The α-axial ligand 5,6-dimethylbenzimidazole (DMB) is involved in organizing the active site to enable histidine-610 to bond with Co, instead of DMB (the reason for the ‘DMB-off’/’His-on’ notation). Binding of histidine-610 residue increases the rate of homolytic β-axial ligand – Co bond breakage by a factor of 1012. Other important residues of methylmalonyl-CoA mutase include Histidine-244, which acts as a general acid near the substrate and shields the radical species from side reactions involving oxygen, Glutamate-370, whose hydrogen bond with the 2’-OH group of the ribose of the β-axial ligand forces interaction between the β-axial ligand radical species and the substrate, and tyrosine-89 which stabilizes reactive radical intermediates and accounts for the stereo-selectivity of the enzyme. The processing protein, MMAA protein, fills the important role of aiding cofactor loading and exchange. MMAA protein favors association with the MCM apoenzyme, and allows for the transfer of the AdoCbl cofactor to the enzyme active site. Furthermore, if the bound AdoCbl accrues oxidative damage during normal functioning, MMAA protein fosters exchange of the damaged cofactor for a new AdoCbl via a GTP-reliant pathway. Interactions MMAA Vitamin B12 MeaB CoA-esters MMAB MMACHC MMADHC References Further reading External links GeneReviews/NIH/NCBI/UW entry on Methylmalonic Acidemia Human proteins EC 5.4.99